eLife (Dec 2021)
Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape
- Fred D Mast,
- Peter C Fridy,
- Natalia E Ketaren,
- Junjie Wang,
- Erica Y Jacobs,
- Jean Paul Olivier,
- Tanmoy Sanyal,
- Kelly R Molloy,
- Fabian Schmidt,
- Magdalena Rutkowska,
- Yiska Weisblum,
- Lucille M Rich,
- Elizabeth R Vanderwall,
- Nicholas Dambrauskas,
- Vladimir Vigdorovich,
- Sarah Keegan,
- Jacob B Jiler,
- Milana E Stein,
- Paul Dominic B Olinares,
- Louis Herlands,
- Theodora Hatziioannou,
- D Noah Sather,
- Jason S Debley,
- David Fenyö,
- Andrej Sali,
- Paul D Bieniasz,
- John D Aitchison,
- Brian T Chait,
- Michael P Rout
Affiliations
- Fred D Mast
- ORCiD
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States
- Peter C Fridy
- ORCiD
- Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States
- Natalia E Ketaren
- ORCiD
- Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States
- Junjie Wang
- Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States
- Erica Y Jacobs
- ORCiD
- Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States; Department of Chemistry, St. John’s University, Queens, United States
- Jean Paul Olivier
- ORCiD
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States
- Tanmoy Sanyal
- ORCiD
- Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States
- Kelly R Molloy
- Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States
- Fabian Schmidt
- Laboratory of Retrovirology, The Rockefeller University, New York, United States
- Magdalena Rutkowska
- Laboratory of Retrovirology, The Rockefeller University, New York, United States
- Yiska Weisblum
- ORCiD
- Laboratory of Retrovirology, The Rockefeller University, New York, United States
- Lucille M Rich
- Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, United States
- Elizabeth R Vanderwall
- Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, United States
- Nicholas Dambrauskas
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States
- Vladimir Vigdorovich
- ORCiD
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States
- Sarah Keegan
- Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States
- Jacob B Jiler
- ORCiD
- Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States
- Milana E Stein
- Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States
- Paul Dominic B Olinares
- ORCiD
- Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States
- Louis Herlands
- AbOde Therapeutics Inc, Woods Hole, United States
- Theodora Hatziioannou
- Laboratory of Retrovirology, The Rockefeller University, New York, United States
- D Noah Sather
- ORCiD
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States; Department of Pediatrics, University of Washington, Seattle, United States
- Jason S Debley
- Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, United States; Department of Pediatrics, University of Washington, Seattle, United States; Division of Pulmonary and Sleep Medicine, Seattle Children’s Hospital, Seattle, United States
- David Fenyö
- ORCiD
- Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States
- Andrej Sali
- ORCiD
- Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States
- Paul D Bieniasz
- ORCiD
- Laboratory of Retrovirology, The Rockefeller University, New York, United States; Howard Hughes Medical Institute, The Rockefeller University, New York, United States
- John D Aitchison
- ORCiD
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States; Department of Pediatrics, University of Washington, Seattle, United States; Department of Biochemistry, University of Washington, Seattle, United States
- Brian T Chait
- ORCiD
- Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States
- Michael P Rout
- ORCiD
- Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States
- DOI
- https://doi.org/10.7554/eLife.73027
- Journal volume & issue
-
Vol. 10
Abstract
The emergence of SARS-CoV-2 variants threatens current vaccines and therapeutic antibodies and urgently demands powerful new therapeutics that can resist viral escape. We therefore generated a large nanobody repertoire to saturate the distinct and highly conserved available epitope space of SARS-CoV-2 spike, including the S1 receptor binding domain, N-terminal domain, and the S2 subunit, to identify new nanobody binding sites that may reflect novel mechanisms of viral neutralization. Structural mapping and functional assays show that indeed these highly stable monovalent nanobodies potently inhibit SARS-CoV-2 infection, display numerous neutralization mechanisms, are effective against emerging variants of concern, and are resistant to mutational escape. Rational combinations of these nanobodies that bind to distinct sites within and between spike subunits exhibit extraordinary synergy and suggest multiple tailored therapeutic and prophylactic strategies.
Keywords
